After seven years of a vigorous fight, Jim Hart worried he was running out of options.

Diagnosed with prostate cancer at age 60, Hart had undergone virtually every treatment — surgery, radiation and hormones — to eradicate it. But a blood test showed that his level of prostate-specific antigen, which should have been undetectable, kept rising ominously. And doctors couldn’t determine where the residual cancer was lurking.

“I didn’t like the sound of that,” said Hart, a retired international oil specialist for the federal government. “I wanted it gone,” he added, especially after learning that he had inherited the BRCA2 gene, making him vulnerable to other cancers.

So when Andrew Joel, Hart’s longtime urologist at Virginia Hospital Center in Arlington, mentioned the hospital’s membership in the Mayo Clinic Care Network and suggested consulting specialists at the Rochester, Minn., hospital for a second opinion, Hart enthusiastically agreed.

A Mayo immunologist told Joel about anew PET scan, not then available in the Washington area, that can detect tiny cancer hot spots. Hart flew to Mayo for the scan, which found cancer cells in one lymph node in his pelvis. He underwent chemotherapy at Virginia Hospital Center and five weeks of radiation at the Mayo Clinic. Since September 2016, there has been no detectable cancer.

Hart’s experience showcases the promise of a much-touted but little understood collaboration in health care: alliances between community hospitals and some of the nation’s biggest and most respected institutions.

For prospective patients, it can be hard to assess what these relationships actually mean — and whether they matter.

Leah Binder, president and chief executive of theLeapfrog Group, a Washington-based patient safety organization that grades hospitals based on data involving medical errors and best practices, cautions that affiliation with a famous name is not a guarantee of quality.

Affiliation agreements are “essentially benefit by association, ” said Gerard Anderson, a professor of health policy and management at the Johns Hopkins Bloomberg School of Public Health. “In some cases it’s purely branding and in other cases it’s a deep association.”

A key question is “how often does the community hospital interact with the flagship hospital? If it’s once a week, that’s one thing. If it’s almost never, that’s another,” Anderson said.

Feeling ‘plugged in’

To expand their reach, flagship hospitals including Mayo, the Cleveland Clinic and Houston’s MD Anderson Cancer Center have signed affiliation agreements with smaller hospitals around the country. These agreements, which can involve different levels of clinical integration, typically grant community hospitals access to experts and specialized services at the larger hospitals while allowing them to remain independently owned and operated. For community hospitals, a primary goal of the brand name affiliation is stemming the loss of patients to local competitors.

In return, large hospitals receive new sources of patients for clinical trials and for the highly specialized services that distinguish these “destination medicine” sites. Affiliations also boost their name recognition — all without having to establish a physical presence.

In some cases, large hospital systems have opted for a different approach, largely involving acquisition. Johns Hopkins acquired Sibley Memorial and Suburban hospitals in the Washington area, along with All Children’s Hospital in St. Petersburg, Fla. The latter was re-christened Johns Hopkins All Children’s Hospital in 2016.

“Every one of these models is different,” said Ben Umansky, managing director for research at the Advisory Board, a Washington-based consulting firm.

Local hospitals, he said, particularly those operating “in the shadows of giants,” may be better able to retain patients “by getting a name brand on their door. . . . There is a sense that they are plugged in.” (Virginia Hospital Center, for example, competes with Hopkins, MedStar Washington Hospital Center, which has an alliance with the Cleveland Clinic, and the Northern Virginia-based Inova system.)

Doctors can obtain speedy second opinions for their patients and streamline visits for those with complex or unusual medical needs, processes that can be daunting and difficult without connections.

Michael Kupferman, senior vice president of the MD Anderson Cancer Network, said it seeks to “elevate the quality of cancer care” by forming partnerships with “high-quality [hospitals] to keep patients at home and provide the imprimatur of MD Anderson.”

Virginia Hospital Center’s association with Mayo is “not just a branding affiliation, it’s a deep clinical affiliation,” said Jeffrey DiLisi, senior vice president and chief medical officer at the Arlington facility.

Despite extensive marketing, many patients seem unaware of the linkage. “We still think a lot about ‘How do we communicate this?’ ” DiLisi said.

Although affiliation agreements differ, many involve payment of an annual fee by smaller hospitals. Officials at Mayo and MD Anderson declined to reveal the amount, as did executives at several affiliates. Contracts with Mayo must be renewed annually, while some with MD Anderson exceed five years.

Acceptance is preceded by site visits and vetting of the community hospitals’ staff and operations. Strict guidelines control use of the flagship name.

“It is not the Mayo Clinic,” said David Hayes, medical director of the Mayo Clinic Care Network, which was launched in 2011. “It is a Mayo clinic affiliate.”

Of the 250 U.S. hospitals or health systems that have expressed serious interest in joining Mayo’s network, 34 have become members.

For patients considering a hospital that has such an affiliation, Binder advises checking ratings from a variety of sources, among them Leapfrog, Medicare, and Consumer Reports, and not just relying on reputation.

“In theory, it can be very helpful,” Binder said of such alliances. “The problem is that theory and reality don’t always come together in health care.”

Case in point: Hopkins’s All Children’s has been besieged by recent reports of catastrophic surgical injuries and errors and a spike in deaths among pediatric heart patients since Hopkins took over. Hopkins’s chief executive has apologized, more than a half-dozen top executives have resigned and Hopkins recently hired a former federal prosecutor to conduct a review of what went wrong.

“For me and my family, I always look at the data,” Binder said. “Nothing else matters if you’re not taken care of in a hospital, or you have the best surgeon in the world and die from an infection.”

In a statement, Commissioner Scott Gottlieb said the agency anticipates more than 200 cell and gene therapy INDs per year by 2020, and 10-20 approvals annually by 2025.

The Food and Drug Administration plans to add 50 new staffers to its clinical review group for cell and gene therapies as it anticipates a surge in new products entering the clinic and the market over the next several years.

In a statement Tuesday, FDA Commissioner Scott Gottlieb said that by next year, the agency will receive on an annual basis more than 200 Investigational New Drug applications – used by companies to get regulatory approval to start clinical trials – and approving 10-20 cell and gene products per year by 2025.

“The activity reflects a turning point in the development of these technologies and their application to human health,” Gottlieb’s statement read. “It’s similar to the period marking an acceleration in the development of antibody drugs in the late 1990s, and the mainstreaming of monoclonal antibodies as the backbone of modern treatment regimens.”

That picture stands in stark contrast to the current roster of approved cell and gene therapies. Those consist of two CAR-T cell therapies for blood cancers – Novartis’s Kymriah (tisagenlecleucel) and Gilead Sciences’ Yescarta (axicabtagene ciloleucel) – and one gene therapy, Spark Therapeutics’ Luxturna (voretigene neparvovec-rzyl), for a rare, inherited form of blindness.

For the application review of Kymriah’s initial approval in August 2017, for acute lymphoblastic leukemia in children and young adults, the agency convened the Oncologic Drugs Advisory Committee, a panel of outside experts who offer advice on approvals when the agency requests it. But it did not do so for Yescarta’s approval two months later for diffuse large B-cell lymphoma in adults, nor did it for Kymriah in DLBCL – the relative ease of the latter approvals indicating the agency had quickly become more comfortable approving the then-unprecedented cell therapies.

But Gottlieb noted there are now more than 800 active INDs for cell and gene therapies on file with the FDA. In a panel discussion at last week’s Biotech Showcase in San Francisco, which coincides with the annual J.P. Morgan Healthcare Conference, Iovance Biotherapeutics CEO Maria Fardis noted that competition in CAR-T therapy is heating up at clinical trial centers, making it harder to recruit patients. She was speaking in the context of CAR-Ts for solid tumors, which remain a much less well-established area of the field than blood cancers. Other types of cell therapies are in development as well, including T-cell receptors and tumor-infiltrating lymphocytes, respectively also known as TCRs and TILs.

Of course, the announcement took place against the background of the ongoing government shutdown. As a result, the FDA is currently only able to perform activities covered by user fees paid before the impasse, but is unable to perform many activities for which user fees had not yet been paid.

Several cell and gene therapy products are expected to reach the market in the near term. Celgene anticipates two CAR-T filings: bb2121 in multiple myeloma; and lisocabtagene maraleucel, which it acquired when it bought Juno Therapeutics last year. Both therapies were touted as near-term opportunities in Bristol-Myers Squibb’s recent $74 billion acquisition of Celgene. Separately, bluebird also anticipates approval in the US by next year for LentiGlobin for transfusion-dependent beta-thalassemia. BioMarin Pharmaceutical also anticipates filing for approval of valoctocogene roxaparvovec in hemophilia A.

For the past few years, US lawmakers have considered legislation that would grant six additional months of market exclusivity for previously approved drugs that have been successfully tested and subsequently approved by the Food and Drug Administration (FDA) for treating rare diseases. This proposal is intended to incentivize pharmaceutical manufacturers to invest in rare disease research.

A new study, released by Health Affairs as a Web First, analyzed the thirteen supplemental applications approved by the FDA that earned rare disease status from 2005 through 2010 to estimate the costs of the clinical trials and potential economic gain arising from a six-month exclusivity extension. According to the authors, Aaron S. Kesselheim, Ben Rome, Ameet Sarpatwari, and Jerry Avorn, the median discounted financial gain for each drug would have been $94.6 million, with blockbuster drugs predictably enjoying the highest returns. The authors’ analysis also suggests that these manufacturers had spent a median of $29.8 million on trials that gained supplemental approval for rare disease indications.

“These results confirm that market exclusivity extensions can generate substantial returns to the manufacturers that are eligible for the incentive — sums that are generally much greater than the cost of performing the requisite clinical trials,” the authors conclude. As a result, “this solution could prove costly to the health care system.” They add, “Any proposal to extend market exclusivity protections in the US prescription drug market should undergo rigorous analysis that weighs the benefits of predicted investment in research against the costs of the incentives to governmental and private-sector payers.”

The authors are all affiliated with the Program on Regulation, Therapeutics, and Law (PORTAL) at the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School.

This study, which was supported by the Laura and John Arnold Foundation, will also appear in Health Affairs’ February issue.

Public debate in the 1990s over drugs’ clinical toxicity has given way to concerns about their financial toxicity. Although drug regulators aren’t supposed to be concerned with pricing, they’ve been drawn into an acrimonious debate over the cost of medicines.